JP2023058608A - 接触活性化系に関連する疾患のタンパク質バイオマーカー - Google Patents
接触活性化系に関連する疾患のタンパク質バイオマーカー Download PDFInfo
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Abstract
Description
本出願は、2017年6月12日に出願された米国仮出願第62/518,492号および2016年9月16日に出願された米国仮出願第62/395,712号の合衆国法典第35編第119条(e)に基づく恩典を主張する。言及されたこれらの出願の各々の全内容が参照により本明細書に組み込まれる。
血漿接触活性化系は、血漿プロテアーゼの一群を伴う炎症促進性および血液凝固促進性の系である。血漿接触活性化系は、外来性の表面もしくは負に荷電した表面に曝されると第XIIa因子によって、あるいは内皮細胞表面上でプロリルカルボキシペプチダーゼによって、活性化される(Sainz I.M. et al., Thromb.Haemost.(2007) 98, 77-83)。接触系の不適切な活性化または無秩序な活性化は、遺伝性血管性浮腫(HAE)を含む様々な疾患に関与している。
本開示は、接触活性化系に関連する疾患を有する対象から得られた生体サンプルでは健康な個体に比べて異なって存在する、またはそのような疾患の異なる段階(例えば、発作対静止状態)の対象から得られた生体サンプルでは異なって存在する、タンパク質の特定に基づく。
接触活性化系は、血液凝固の内因性経路を開始させ、炎症促進性ペプチドであるブラジキニンの遊離を介して炎症を促進する。ハーゲマン因子としても知られている第XII因子(FXII)は、血液凝固の内因性経路ならびにカリクレイン-キニン系の活性化において役割を担うセリンプロテアーゼである。FXIIは、負に荷電した表面(例えば、ポリアニオン性の表面、ガラス、ポリホスフェート、エラグ酸)によって活性化されて、活性形態であるFXIIaを生じる。活性化されたFXIIaは、プレカリクレインを切断する能力を有し、活性型pKalを生じさせる。その後、活性化されたpKalはFXIIを切断してFXIIaにすることができ、FXIIaがさらに多くのpKalを生じさせ、これがさらなるFXIIをさらに活性化してFXIIaにする、正のフィードバックループがもたらされる。活性化されたpKalはまた、高分子量キニノーゲン(HMWK)を切断してブラジキニンを遊離させることもできる。HAEなど、接触系の活性化に関連する疾患では、ブラジキニンのレベルの増加が、浮腫性HAE発作をもたらす血管拡張と炎症を誘発し得る。例えば、接触活性化系によって媒介されるような疾患を特定するために、そのような疾患を有するかそのような疾患を有するリスクがある対象を特定するために、使用できる新規のバイオマーカーを特定することが望ましい。
本明細書で説明される方法およびキットは、HAEを有する対象からのサンプルでは健康な対象からのサンプルと比べて異なって存在することが、および/またはそのような疾患の異なる段階(例えば、基礎的状態対発作)の対象からのサンプルでは異なって存在することが、見出されたタンパク質の特定に少なくとも部分的に基づく。本明細書で使用される場合、用語「タンパク質バイオマーカー」または「タンパク質バイオマーカーのセット」は、異なる対象群からのサンプルでは異なるレベルで存在するタンパク質またはタンパク質のセットを指す(例えば、接触系に関連する疾患を有する対象対健康な対象(例えば、疾患を有さない対象)、または疾患を有するが静止段階にある対象対疾患の発作中の対象)。そのようなバイオマーカー/バイオマーカーのセットは、診断/予後診断の用途および(例えば研究を目的とする)非臨床用途の両方で使用されてよい。
本開示の一態様は、接触活性化系に関連する疾患を有する、有することが疑われる、またはそのリスクがある、対象(例えば、ヒト患者)から得られたサンプルを、そのサンプルにおける本明細書で説明されるようなバイオマーカーのセットのレベルを測定することによって分析するための方法に関する。そのようなアッセイ法から得られた結果は、診断および/または予後診断の用途ならびに他の非臨床用途(研究用途など)に有用であろう。
本明細書で説明される方法は、対象から得られた生体サンプルを用意することを伴う。本明細書で使用される場合、「生体サンプル」は、対象からの組織(例えば、血液、血漿またはタンパク質)を含む組成物を指す。サンプルには、対象から採取された最初の未処理サンプルならびにその後に処理された(例えば、部分的に精製または保存された)形態の両方が包含される。例示的なサンプルには、血液、血漿、涙、または粘液が包含される。一部の実施形態において、サンプルは、血清サンプルまたは血漿サンプルなどの体液サンプルである。一部の実施形態では、例えば疾患の進行を評価するか治療の有効性を評価するために、複数(例えば、少なくとも2つ、3つ、4つ、5つ、または6つ以上)の生体サンプルが経時的に、または特定の時間間隔で、対象から採取されてよい。
対象からのサンプルにおいて検出された表1に提示されるタンパク質のレベルは、接触活性化系に関連する疾患(例えば、HAE)を診断するための、そのような疾患の進行をモニタリングするための、疾患に対する治療の有効性を評価するための、特定の治療に適している患者を特定するための、および/または対象における疾患の発作を予測するための、信頼性の高いバイオマーカーとして使用できる。
さらに、本明細書で説明されるバイオマーカーのセットのうちのいずれかのレベルは、研究目的で使用されてよい。接触活性化系に関連する疾患が多数特定されているが、他の疾患が、類似するメカニズムによって媒介される、または類似するコンポーネントを伴う、という可能性がある。一部の実施形態において、本明細書で説明される方法は、疾患を接触活性化系に、または接触活性化系のコンポーネントに、関連すると特定するために使用されてよい。一部の実施形態において、本明細書で説明される方法は、疾患のメカニズム(例えば、疾患の発症に関与する新規の生物学的経路またはプロセスの発見)または進行を研究するために使用されてよい。
本開示はまた、本明細書で説明されるようなバイオマーカーのセットのレベルの測定における使用のためのキットおよび検出装置も提供する。そのようなキットまたは検出装置は、タンパク質バイオマーカー(表1に列挙されるものなど)に特異的に結合する結合物質を含んでよい。例えば、そのようなキットまたは検出装置は、表1から選択される2つの異なるタンパク質バイオマーカーに対して特異的である少なくとも2種の結合物質を含んでよい。一部の例では、キットまたは検出装置は、本明細書で説明されるタンパク質バイオマーカーのセットの全てのメンバーに対して特異的な結合物質を含む。
本明細書で説明される方法を用いて特定された、接触活性化系に関連する疾患のリスクがあるかそれに罹患している対象は、任意の適切な治療薬で治療されてよい。一部の実施形態において、提供される方法は、説明される方法(例えば、バイオマーカーのセットのレベルの測定)のアウトプットに基づいて対象に対する治療を選択することを含む。
血漿カリクレイン結合物質(例えば結合タンパク質、例えばポリペプチド、例えば阻害性ポリペプチド、例えば抗体、例えば阻害性抗体、または他の結合物質(例えば小分子))は、様々な疾患および状態(例えば、血漿カリクレイン活性と関わる疾患および状態)に対して有用な治療薬である。例えば、一部の実施形態では、血漿カリクレイン活性と関わる疾患および状態は、遺伝性血管性浮腫(HAE)である。一部の実施形態において、血漿カリクレイン阻害剤などの血漿カリクレイン結合物質は、接触活性化系に関連する疾患のリスクがあるかそれに罹患している対象に投与される。
EVQLLESGGG LVQPGGSLRL SCAASGFTFS HYIMMWVRQA PGKGLEWVSG IYSSGGITVY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAYRR IGVPRRDEFD IWGQGTMVTV SS
DIQMTQSPS TLSASVGDRV TITCRASQSI SSWLAWYQQK PGKAPKLLIY KASTLESGVP SRFSGSGSGT EFTLTISSLQ PDDFATYYCQ QYNTYWTFGQ GTKVEI
一部の実施形態では、ブラジキニンB2受容体阻害剤(例えば、アンタゴニスト)が対象に投与される。例示的なブラジキニンB2受容体アンタゴニストには、ブラジキニンB2受容体への天然ブラジキニンの結合をブロックする10個のアミノ酸を含むペプチド模倣薬であるイカチバント(フィラジル(登録商標))が包含される。
一部の実施形態では、C1-INH補充薬などのC1エステラーゼインヒビター(C1-INH)が対象に投与される。例示的なC1-INH補充薬は公的に利用可能であり、これらには、例えば、ヒト血漿由来C1-INH(例えば、ベリナート(登録商標)およびシンライズ(登録商標))が包含される。
実施例1:HAE患者からのサンプルでは健康な個体に比べて異なって存在するタンパク質の特定
健康な個体(N=22;「正常」サンプルと呼称される)から、ならびに疾患の静止状態の間のHAE(I型/II型)を有する患者(N=33;「基礎」と呼称される)および発作中のHAE(I型/II型)を有する患者(N=33;「発作」と呼称される)から、血漿サンプルを採取した。翼状針、プラスチック製カテーテルおよびプラスチック製採取管を用いた静脈穿刺によって血液を採取する厳密な血液採取プロトコルに従った。最初の採血管はセラムチューブであったが、これは廃棄された。プロテアーゼ阻害剤カクテルと抗凝固剤とを含む第2の採血管(P100チューブ)をプロテオーム解析のために使用した。P100チューブに採取された血液を、採取から1時間以内に処理して血漿にし、いくつかのアリコートに分け、-70℃未満で凍結した。
本明細書で開示される特徴は全て、任意の組み合わせで組み合わされてよい。本明細書で開示される特徴はそれぞれ、同じ目的、同等の目的または類似の目的を果たす代替的な特徴で置き換えられてよい。従って、特に明記しない限り、開示される特徴はそれぞれ、一般的な一連の同等または類似の特徴の一例に過ぎない。
当業者であれば、本明細書で説明される本開示の特定の実施形態に対する多くの均等物を認識する、またはただの通例に過ぎない実験法を用いてそれらを確認することができるであろう。本開示の範囲は、上記の説明に限定されることを意図されず、むしろ添付の特許請求の範囲に記載される通りである。
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WO2015061183A1 (en) * | 2013-10-21 | 2015-04-30 | Dyax Corp. | Assays for determining plasma kallikrein system biomarkers |
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US20240142468A1 (en) | 2024-05-02 |
US20210285962A1 (en) | 2021-09-16 |
US11815516B2 (en) | 2023-11-14 |
BR112019005179A2 (pt) | 2019-07-02 |
KR20230044024A (ko) | 2023-03-31 |
WO2018053244A1 (en) | 2018-03-22 |
AU2024201506A1 (en) | 2024-03-28 |
CN109716138B (zh) | 2023-10-03 |
IL265195A (en) | 2019-05-30 |
CN109716138A (zh) | 2019-05-03 |
CO2019002599A2 (es) | 2019-03-29 |
MX2019002932A (es) | 2019-07-15 |
JP2019529906A (ja) | 2019-10-17 |
JP7412616B2 (ja) | 2024-01-12 |
CN117192130A (zh) | 2023-12-08 |
AU2017325983A1 (en) | 2019-03-21 |
CA3037154A1 (en) | 2018-03-22 |
KR102513485B1 (ko) | 2023-03-23 |
JP7225089B2 (ja) | 2023-02-20 |
EP3513196A1 (en) | 2019-07-24 |
KR20190053913A (ko) | 2019-05-20 |
JP2024023904A (ja) | 2024-02-21 |
NZ751193A (en) | 2024-02-23 |
AU2017325983B2 (en) | 2023-12-07 |
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